The invasive growth of epithelial cancers is associated with characteristic cellular and molecular changes in the supporting stroma. For example, epithelial cancers induce the formation of tumor blood vessels, the recruitment of reactive tumor stromal fibroblasts, lymphoid and phagocytic infiltrates, the release of peptide mediators and proteolytic enzymes, and the production of an altered extracellular matrix (ECM). See, e.g., Folkman, Adv. Cancer Res. 43: 175-203 (1985); Basset et al., Nature 348: 699-704 (1990); Denekamp et al., Cancer Metastasis Rev. 9: 267-282 (1990); Cullen et al., Cancer Res. 51: 4978-4985 (1991); Dvorak et al., Cancer Cells 3: 77-85 (1991); Liotta et al., Cancer Res. 51: 5054s-5059s (1991); Garin-Chesa et al., J. Histochem. Cytochem. 37: 1767-1776 (1989). A highly consistent molecular trait of the stroma in several common histologic types of epithelial cancers is induction of the fibroblast activation protein (FAPα), a cell surface glycoprotein with an observed Mr of 95,000 originally discovered with a monoclonal antibody, mAb F19, raised against proliferating cultured fibroblasts. See Rettig et al., Cancer Res. 46: 6406-6412 (1986); Rettig et al., Proc. Natl. Acad. Sci. USA 85: 3110-3114 (1988); Garin-Chesa et al., Proc. Natl. Acad. USA 87: 7235-7239 (1990); Rettig et al., Cancer Res. 53: 3327-3335 (1993). Each of these four papers is incorporated by reference in its entirety.
Immunohistochemical studies such as those cited supra have shown that FAPα is transiently expressed in certain normal fetal mesenchymal tissues but that normal adult tissues are generally FAPα−. Similarly, malignant epithelial, neural and hematopoietic cells are generally FAPα−. However, most of the common types of epithelial cancers, including >90% of breast, lung, skin, pancreas, and colorectal carcinomas, contain abundant FAPα+ reactive stromal fibroblasts. Garin-Chesa et al., Proc. Natl. Acad. Sci. USA 87: 7235-7239 (1990). The FAPα+ tumor stromal fibroblasts almost invariably accompany tumor blood vessels, forming a distinct cellular compartment interposed between the tumor capillary endothelium and the basal aspect of malignant epithelial cell clusters. While FAPα+ stromal fibroblasts are found in both primary and metastatic carcinomas, benign and premalignant as epithelial lesions, such as fibroadenomas of the breast and colorectal adenomas only rarely contain FAPα+ stromal cells. In contrast to the stroma-specific localization of FAPα in epithelial neoplasms, FAPα is expressed in the malignant cells of a large proportion of bone and soft tissue sarcomas. (Rettig et al., Proc. Natl. Acad. Sci. USA 85: 3110-3114 (1988)). Finally, FAPα+ fibroblasts have been detected in the granulation tissue of healing wounds (Garin-Chesa et al., supra). Based on the restricted distribution pattern of FAPα in normal tissues and its uniform expression in the supporting stroma of many epithelial cancers, clinical trials with 131I-labeled mAb F19 have been initiated in patients with metastatic colon cancer (Welt et al., Proc. Am. Assoc. Cancer Res. 33: 319 (1992); Welt et al. J. Clin. Oncol. 12: 1561-1571 (1994)) to explore the concept of “tumor stromal targeting” for immunodetection and immunotherapy of epithelial cancers.
Rettig et al., Int. J. Cancer 58: 385-392 (1994), incorporated by reference, discusses the FAPα molecule and its features. Rettig et al postulate that FAPα is found in high molecular weight complexes in excess of 400 kilodaltons, but do not discuss the possibility of dimeric molecules, nor does the paper elaborate on the specific enzymatic properties of the molecule.
The induction of FAPα+ fibroblasts at times and sites of tissue remodeling during fetal development, tissue repair, and carcinogenesis is consistent with a fundamental role for this molecule in normal fibroblast physiology. Thus, it is of interest and value to isolate and to clone nucleic acid molecules which code for this molecule. This is one aspect of the invention, which is described in detail together with other features of the invention, in the disclosure which follows. Further aspects of the invention include the dimeric FAPα molecules, and the exploitation of the properties of these molecules. These features are also elaborated upon hereafter.